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Slippery and Slimy Semaglutide Origin

Venomous bites and stings from spiders, scorpions, snakes, lizards, and jellyfish—even caterpillars, snails, and octopuses—affect millions and cause thousands of deaths annually worldwide.

However, these animal venoms are on the brink of revolutionizing medicine, offering new treatments for conditions ranging from cancer to heart disease, and even slowing down aging.

This is not just a distant possibility. Already, a potent animal venom is behind the popular weight-loss drug semaglutide, known as Wegovy and Ozempic.

Furthermore, viper venom is the basis for ACE inhibitors, medications used by thousands in the UK for high blood pressure.

Ozempic and Wegovy generated an impressive £15 billion last year, with endorsements from celebrities like Sharon Osbourne, Boy George, and Elon Musk.

The key to these weight-loss drugs’ success lies in the venom of the Gila monster, a 2-foot-long venomous lizard native to the US.

Human fatalities from Gila monster bites are rare, but in Colorado earlier this year, Christopher Ward, 34, died from complications after being bitten by one he was keeping illegally as a pet.

A bite from this reptile can cause swelling, intense burning pain, vomiting, dizziness, a rapid heart rate, and low blood pressure. Yet, Gila venom also stimulates the pancreas, which produces insulin to regulate hunger and blood sugar.

Nearly 35 years ago, Dr. John Eng, an endocrinologist at the Veterans Affairs Medical Center in New York, discovered that a chemical in the venom could serve a dual purpose—as both a poison and a hormone regulator.

Dr. Eng identified a small protein in the venom called exendin-4, similar to the human hormone GLP-1, which regulates insulin and appetite. While GLP-1 is active for about two minutes in the human body, exendin-4 remains active for hours, suggesting a long-lasting effect on blood sugar and appetite.

In 2005, Dr. Eng’s research led to the development of exenatide, the first GLP-1 mimicking drug, marketed as Byetta.

Competing pharmaceutical companies aimed to improve on exenatide, with semaglutide by Novo Nordisk emerging as a clear winner. Semaglutide, marketed as Ozempic and Wegovy, proved highly effective for treating type 2 diabetes and as a weight-loss drug.

This success has inspired scientists to explore venoms for new therapies, a field known as venomics.

With more than 220,000 venomous species, each with unique venoms, the potential for medical breakthroughs is vast.

For example, Australian octopus venom is being developed into a drug, Octpep-1, to stop melanoma tumors from growing. Dr. Maria Ikonomopoulou, head of the Translational Venomics Group at the IMDEA Food Institute in Madrid, is leading this research. Octpep-1 targets cancer cells specifically, minimizing effects on healthy cells—a significant advantage over current treatments.

The venom of the Australian funnel web spider, containing over 3,000 active chemicals, shows promise in treating heart attacks and strokes. Researchers at Queensland University found that a substance in the venom, Hi1a, could protect heart and brain cells from damage caused by a lack of oxygen, potentially reducing the impact of heart attacks and strokes.

Snake venoms have long been of interest, with the saw-scaled viper’s venom leading to the development of tirofiban, a drug that prevents blood clots. This viper, responsible for the most snakebite deaths globally, produces venom that causes internal hemorrhaging. Scientists at Temple University School of Medicine discovered that a chemical in the venom, echistatin, could prevent human blood platelets from clotting, leading to the creation of tirofiban.

Cone snail venom has led to ziconotide, a powerful painkiller used for severe chronic pain. The cone snail’s venom, capable of paralyzing fish, has been harnessed to create a drug that blocks pain signals to the brain. However, due to its potent effects, ziconotide is administered through a small pump directly into the spinal cord fluid, reserved for patients with extreme pain conditions like cancer.

Even caterpillar venom is being studied for its potential to deliver life-saving drugs directly into human cells. The venom of the asp caterpillar, known for its painful sting, contains a protein that can create openings in cells. This mechanism could allow targeted delivery of potent cancer drugs, sparing healthy cells and minimizing side effects.

Moreover, venoms from marine animals are being explored for anti-aging treatments. Dr. Ikonomopoulou’s research includes targeting “zombie cells” in the body—cells that are alive but function improperly. Venom-derived drugs could potentially rejuvenate these cells, offering new avenues for combating the effects of aging.

Venom-derived medicines represent a cutting-edge frontier in pharmaceuticals, with researchers continuously uncovering new therapeutic uses for these natural toxins. As scientists delve deeper into the complexities of venoms, the potential for groundbreaking treatments and life-saving drugs continues to expand, promising a future where nature’s deadliest substances become some of our most potent allies in medicine.

Pharmaceutical drug pricing and reimbursement remain a prominent topic in national discussions. In recent news, Maryland’s Prescription Drug Affordability Board (PDAB) has finalized its selection of drugs for affordability review. The board will conduct a comprehensive “cost review,” gathering public comments, additional information, and data over a 60-day period to determine if the chosen drugs will be subject to state-prescribed upper payment limits.

Background:

Responding to the escalation of prescription costs and overall state healthcare spending, 11 states, including Maryland and Colorado, have established drug affordability review boards to assess certain high-cost prescription drugs, both brand and generic. Another 12 states are considering similar legislation. Currently, Colorado and Maryland are the only states with selected drugs for affordability review.

In 2019, Maryland’s General Assembly passed a groundbreaking law establishing the PDAB. Empowered by the Assembly, the PDAB is tasked with studying the pharmaceutical delivery and payment process, accessing data on drug pricing and usage, and developing regulations. The board also has the authority to set “upper payment limits.” In March 2024, the board identified eight drugs for “cost review,” ultimately proceeding with six after removing Biktarvy and Vyvanse from the list.

During its May 20 meeting, the board emphasized that selecting a drug for affordability review doesn’t imply it’s unaffordable. Instead, it allows the board to gather information on patient costs and financial metrics for an affordability determination. However, this offers no relief for drug manufacturers facing potential state-mandated upper payment limits.

The board plans to discuss the findings of its cost review at the next meeting scheduled for July 22. Based on this review, it will determine if the drugs have caused or will cause affordability challenges for the state healthcare system or high out-of-pocket costs for patients.

Before setting an upper payment limit for any drug, the PDAB must finalize its implementation plan and gain approval from the General Assembly’s Legislative Policy Committee (LPC). If the LPC doesn’t approve the plan within 45 days, it goes to the governor and Attorney General for approval.

Implementing upper payment limits may pose challenges, such as adjusting drug formularies and claims systems for insurance carriers. The Colorado Association of Health Plans (CAHP) raised concerns about the associated costs outweighing potential savings.

Notably, one PDAB member anticipates legal challenges from drugmakers regarding setting upper payment limits on drugs covered by state and local government health plans.

Key Takeaways:

The fate of state-prescribed upper payment limits remains uncertain. While some states move forward with drug selection and review, manufacturers have challenged such laws in court. The outcome of these legal battles is unpredictable, prompting pharmaceutical companies to carefully evaluate their product portfolios and prepare for potential future developments.

How We Can Help:

Morgan Lewis will continue to monitor state drug affordability review developments. We provide strategic guidance to pharmaceutical manufacturers navigating federal and state government pricing complexities, assisting them in addressing these intricate issues.

CHICAGO – Semaglutide, a drug used for diabetes and weight loss, has been linked to a significantly higher risk of repeat operations in diabetes patients undergoing lumbar surgery, according to a new study.

The risk for additional surgeries increases with prolonged use of the popular weight loss and diabetes medication.

Investigators say this study is the first to provide evidence on the impact of semaglutide on spine surgery outcomes.

“We expected better postoperative outcomes, including fewer wound complications, but instead, we found increased odds of needing additional surgeries in our diabetic patients,” said Dr. Syed I. Khalid, a neurosurgery resident at the University of Illinois Chicago, in an interview with Medscape Medical News.

The findings were presented on May 3 at the American Association of Neurological Surgeons (AANS) 2024 Annual Meeting.

Additional Surgery at Year 1

The study utilized the all-payer Mariner database to identify patients aged 18-74 with type 2 diabetes who underwent elective one- to three-level transforaminal lumbar interbody fusions (TLIFs) between January 2018 and October 2022. Patients were matched 3:1 for age, sex, hypertension, obesity, smoking history, chronic kidney disease, osteoporosis, insulin use, and spinal fusion level, resulting in 447 patients using semaglutide and 1334 not using it. Over half (56%) were female, 62% used insulin, and 81% underwent single-level TLIF.

Total medical complications were higher in the semaglutide group at 13.4% compared to 7.7% in the non-semaglutide group (odds ratio [OR], 1.85). This increase was due to higher rates of urinary tract infections (6.7% vs. 2.5%) and acute kidney injuries (6.3% vs. 3.9%), complications previously observed with semaglutide, Khalid said. However, total surgical complications were lower in the semaglutide group at 3.8% versus 5.2% in the non-semaglutide group (OR, 0.73).

Patients on semaglutide experienced fewer wound healing complications (5 vs. 31), hematomas (1 vs. 9), surgical-site infections (12 vs. 44), and cerebrospinal fluid leaks (2 vs. 3).

Nonetheless, semaglutide users were nearly 12 times more likely to require an additional lumbar surgery within a year compared to non-users (27.3% vs. 3.1%; OR, 11.79; 95% CI, 8.17-17.33).

Kaplan-Meier plots showed a significant divergence in outcomes based on semaglutide exposure of more than or less than nine months (log-rank P < .0001).

Currently under review for publication, this study provides the first evidence on semaglutide’s impact on spine surgery, Khalid said. A follow-up study, also under review, examines morbidly obese patients without diabetes who took semaglutide for weight loss and showed a similar trend.

Sarcopenia the Cause?

The additional surgeries were primarily extensions of constructs, with more levels requiring fusion, Khalid noted.

“One hypothesis is that muscle loss, or sarcopenia, in conjunction with fat loss might be causing these issues,” Khalid explained.

The mechanism remains speculative, but other studies have shown that patients with frailty, weaker bones, and sarcopenia have worse outcomes with spine surgery.

The researchers plan to use artificial intelligence to evaluate changes in body composition after semaglutide use in patients who underwent imaging prior to spine surgery or even before back pain occurred. Since these medications are uptitrated over time, follow-up studies will investigate whether these changes occur at specific doses, Khalid added.

Based on this analysis of generic semaglutide, it is not yet clear whether other glucagon-like peptide 1 (GLP-1) receptor agonists will yield similar findings, but “the odds of a class effect are high,” Khalid said.

Commenting on the findings, Dr. Walavan Sivakumar, director of neurosurgery at Pacific Neuroscience Institute, noted that recent guidance from the American Society of Anesthesiologists recommends stopping GLP-1 receptor agonists before elective surgery to reduce anesthesia-related complications.

“It’s an incredibly topical point and appears to be a daily concern for clinicians in neurosurgery,” Sivakumar said. “This study is thought-provoking and a great first step.”

Sivakumar also observed that frailty is a critical issue in neurosurgery. “It significantly impacts all surgical outcomes and is currently a major focus of study in neurosurgical research.”

It’s remarkable how willing some doctors have been to prescribe diabetes drugs like Ozempic and Wegovy off-label for weight loss. However, some patients have found alternative ways to obtain these medications. This year, there have been several reports of counterfeit versions of these weight loss injectables, with multiple patients hospitalized due to adverse reactions.

The risks don’t end there. This week, the FDA announced the recall of 751 units of tirzepatide on April 20, 2024. Tirzepatide is the active ingredient in diabetes and weight-loss drugs Mounjaro and Zepbound, popular brands in this medication class. A 2021 study in the New England Journal of Medicine suggested that Mounjaro might be superior to semaglutide—used in Ozempic and Wegovy—for controlling blood sugar and potentially appetite and weight loss.

Revive Rx Pharmacy, a Texas-based company, appears to be the manufacturer of the recalled 10-milligram multi-dose tirzepatide vials, along with two-milliliter doses of compounding sterile solution. According to the FDA report, the recall was due to a “label mix-up,” revealing a serious issue: vials labeled as tirzepatide actually contained testosterone cypionate.

Yes, vials labeled as tirzepatide contained testosterone. The FDA reported that the mislabeled drug was distributed nationwide in the USA but did not specify particular regions or organizations. The recalled tirzepatide has the following identifiable details:

• Lot #: 748127
• Expiration: 9/24/2024

The FDA has classified this as a Class I recall.

FDA Recall Classifications:

• Class I Recall: The most severe, issued for products that could cause serious health issues or death.
• Class II Recall: Involves products that may cause temporary or medically reversible adverse health effects.
• Class III Recall: For products unlikely to cause health problems but that fail to comply with FDA labeling or manufacturing regulations.

Dr. Tricia Varacallo, DO, a contributor to The Healthy by Reader’s Digest, lists potential health consequences for individuals unknowingly administering testosterone:

1. Diabetes management: Patients missing out on tirzepatide for diabetes could experience uncontrolled blood sugar levels, leading to serious conditions like diabetic ketoacidosis, cardiovascular disease, nerve damage, and other severe complications.
2. Unintended hormone exposure: Patients receiving testosterone cypionate instead of tirzepatide might face elevated testosterone effects. Testosterone influences muscle mass, fat distribution, and bone density. Inappropriate use can cause hormonal imbalances, mood swings, increased aggression, skin issues, and changes in sexual function. For those not prescribed testosterone, exposure could lead to severe side effects like cardiovascular issues or liver problems. It is particularly serious for pregnant women or individuals with hormone-sensitive cancers (e.g., breast or prostate cancer). Affected individuals should consult their healthcare provider immediately.
3. Lack of expected weight loss: This could be frustrating and harmful for patients relying on the medication as part of a weight management plan, potentially causing emotional distress or setbacks in their health goals.

Revive Rx did not immediately respond to The Healthy’s request for comment.

A new study suggests that popular weight-loss medications Ozempic and Wegovy (both containing semaglutide) might work by enhancing taste sensitivity, leading people to crave sweets less.

Researchers presented their findings at the Endocrine Society’s annual meeting, indicating that semaglutide appears to influence how the tongue and brain process sweet flavors.

“People with obesity often have a dulled sense of taste and a stronger desire for sugary, high-calorie foods,” explained lead researcher Mojca Jensterle Sever, an endocrinologist from Slovenia.

The study involved obese women who were randomly assigned either semaglutide injections or a placebo for four months. Researchers monitored their taste sensitivity using taste strips with varying intensity levels. Brain activity in response to a sweet solution was also tracked using MRI scans before and after meals. Additionally, tongue tissue samples were analyzed to assess genetic activity.

Women taking semaglutide exhibited changes in taste perception, gene expression in taste buds, and brain response to sweetness. These alterations mirrored observations in animal studies.

“These findings may correlate with patient reports about changes in food preferences, beyond just the general appetite and satiety effects that aid weight loss,” Jensterle Sever commented.

However, the researcher emphasized the need for further studies due to the lab setting and individual variations in taste perception. Future research will determine if semaglutide’s effectiveness hinges on taste modifications.

It’s important to note that findings presented at medical meetings are considered preliminary until published in peer-reviewed journals.